We are in the midst of an obesity epidemic, which is also leading to an epidemic of type 2 diabetes (T2D). Approximately half the heritability of diabetes susceptibility is due to genetic variation. Recent human genetic studies suggest that human diabetes is polygenic and that genes that contribute to diabetes susceptibility primarily affect -cell function rather than insulin action. The relationship between obesity and T2D exhibits the following dichotomy, which is at the heart of the diabetes field: >80% of people with T2D are obese and insulin resistant. However, most obese people do not develop T2D. This obesity/diabetes dichotomy was replicated in mice by studying two mouse strains (C57BL/6 & BTBR) that differ in diabetes induced by obesity. An F2 was created between the two strains and several quantitative trait loci (QTLs) controlling plasma glucose and insulin were mapped to high resolution, thereby identifying the genes underlying the QTLs. Tomosyn-2 is a major gene contributing to diabetes susceptibility of the BTBR mouse strain. The preliminary data show that Tomosyn-2 is an inhibitor of insulin secretion. The project has identified phosphorylation sites on Tomosyn-2 that are responsive to insulin secretagogues, and a SNP that affects the stability of the Tomosyn-2 protein. The overall hypothesis to be tested is that Tomosyn-2 imposes a break on insulin secretion that is relieved by secretagogue-induced signaling pathways. This hypothesis will be tested by pursuing four specific aims: 1) to identify the signaling pathways and phosphorylation sites involved in regulating Tomosyn-2; 2) to elucidate the mechanistic consequences of Tomosyn-2 phosphorylation; 3) to elucidate the mechanism by which Tomosyn-2 regulates insulin granule exocytosis; and 4) to discover the role of Tomosyn-2 interacting partners in the regulation of insulin secretion. An innovative feature of the work is that it studies an allelic variant with disrupted regulation. These studies will elucidate how beta cells prevent hypoglycemia by imposing a brake on insulin secretion and how this brake is lifted in response to insulin secretagogues. It will identify pathways that when disrupted can lead to increased susceptibility to obesity-induced type 2 diabetes.